Mechanisms and Duration of Immunity to SARS-CoV-2

在美国，每2000人中就有1人患有原发性免疫缺陷疾病（PID），是非霍奇金淋巴瘤患病率的两倍。PID患者有感染严重COVID-19和疫苗接种反应受损的风险。对这些个体进行疫苗强化研究显然对公共卫生具有重要意义。对这些患者的研究提供了宝贵的机会，将基因型与人类的免疫表型联系起来，其中许多患者的表型是单基因先天原因造成的。Boyd博士将与纽约西奈山医学院（Mount Sinai School of Medicine）的全球PID专家Charlotte Cunningham-Rundles博士合作，分析血清学、B淋巴细胞和T淋巴细胞对疫苗接种的反应，并使用先前收集的142名PID患者的血浆和外周血单个核细胞，这些患者的疾病影响了不同程度的适应性免疫反应。其免疫表型除了保护性免疫受损外还包括自身反应性。该队列中最常见的诊断是常见可变免疫缺陷（CVID）。这些患者产生次优的疫苗反应，但有些人在接种疫苗后仍能产生特异性抗体滴度。我们将对这些患者的血清学反应和B细胞和T细胞群进行深入的系统免疫学表征，表征频率、细胞表型、B细胞和T细胞受体序列，以及抗原特异性B细胞靶向的抗原表位，使用14种不同的dna标记的SARS-CoV-2变异抗原四聚体。对PID患者T细胞反应的检查将包括疫苗抗原刺激T细胞频率和TCR序列的分析，以及详细的流式细胞术免疫表型分析。这些数据将为PID患者的SARS-CoV-2疫苗接种和增强应答提供临床相关信息，随着新的含Omicron变体的疫苗增强剂的实施，可能有助于临床指导，并应提供对人类患者mRNA接种后促进适应性免疫应答和记忆形成的免疫基因、途径和细胞群的见解。

Primary immune deficiency disorders (PID) affect 1 in 2,000 individuals in the U.S., twice the prevalence of non-Hodgkin lymphoma. PID patients are at risk for severe COVID-19 and impaired responses to vaccination. Research into vaccine boosting in these individuals is clearly of importance for public health. Study of these patients, many of which have single-gene inborn causes for their phenotype, offers the valuable opportunity to correlate genotypes with immunological phenotypes in humans. Dr. Boyd will collaborate with Dr. Charlotte Cunningham-Rundles, a world expert in PID at the Mount Sinai School of Medicine in New York, to analyze the serological and B and T lymphocyte responses to vaccination and boosting using previously-collected plasma and peripheral blood mononuclear cells from a cohort of 142 PID patients whose disorders affect adaptive immune responses with a range of severity, and whose immunological phenotypes can include autoreactivity in addition to impaired protective immunity. The most common diagnosis in this cohort is Common Variable Immune Deficiency, (CVID). These patients generate suboptimal vaccine responses, but some can still mount specific antibody titers after vaccination. We will carry out an in-depth systemsimmunology characterization of serological responses and B cell and T cell populations in these patients, characterizing the frequencies, cellular phenotypes, B cell and T cell receptor sequences, and antigen epitopes targeted by antigen-specific B cells, using a panel of 14 different DNA-tagged SARS-CoV-2 variant antigen tetramers. Examination of T cell responses in the PID patients will include analysis of vaccine antigen-stimulated T cell frequencies and TCR sequences, and detailed flow cytometric immunophenotyping. These data will provide clinically relevant information about SARS-CoV-2 vaccination and boosting responses in PID patients to potentially contribute to clinical guidance as new Omicron variant-containing vaccine boosters are implemented, and should provide insights into the immunological genes, pathways and cell populations that contribute to adaptive immune responses and memory formation after mRNA vaccination in human patients.